Biomedical subjects

Torbjörn Lundstedt

Publications and source records attributed to Torbjörn Lundstedt.

12 recordsLinked to original sources

PubMed2006

Presentation of a structurally diverse and commercially available drug data set for correlation and benchmarking studies.

A multivariate analysis of drugs on the Swedish market was the basis for the selection of a small, physicochemically diverse set of 24 drug compounds. Factors such as structural diversity, commercial availability, price, and a suitable analytical technique for quantification were considered in the selection. Lipophilicity, pKa, solubility, and permeability across human Caco-2 cell monolayers were measured for the compiled data set. The results show that, by use of a physicochemically diverse data set, experimental responses over a wide range were obtained. The paper also shows how experimental difficulties due to the diversity of the data set can be overcome. We anticipate that this data set can serve as a benchmark set for validation of new experimental techniques or in silico models. It can also be used as a diverse starting data set for the development of new computational models.

Caco-2 Cells↗

PubMed2006

Multivariate methods in the development of a new tablet formulation: excipient mixtures and principal properties.

A tablet formulation for direct compression has previously been studied using multivariate design. An optimization study of one of the most important tablet properties, disintegration time, revealed that excipients with Principal Properties (PP's) that were predicted as suitable by the model were not represented within the studied material. The feasibility of using mixtures of excipients in the multivariate approach to tablet formulation to solve this problem has been investigated in the present study. By mixing different excipients of the same excipient class, it should be possible to obtain mixtures with the predicted PP's, which in turn should give a formulation with the desired properties. In order to investigate the utility of this approach, separate mixture designs were applied to both binders and fillers (diluents). As reported here, the Partial Least Squares Projections to Latent Structures (PLS) model developed in the previously published screening study has been validated in the sense that the interesting region of the PP space identified in it has been shown to contain excipients, pure or mixed, that give the formulation suitable properties. Formulations with suitable properties were found with the mixture experiments. The local models also offer several alternatives for the composition of the formulation that yield the desired disintegration time.

Chemistry, Pharmaceutical↗

PubMed2006

Robustness testing of a tablet formulation using multivariate design.

A total of 45 experiments were carried out to evaluate the robustness of two similar tablet formulations--a product of two strengths--with respect to normal batch-to-batch variation of the excipients and the active pharmaceutical ingredient. The formulations consist of 10 ingredients. Because of the differing amounts of active pharmaceutical ingredients, the two formulations also differ in the amounts of two of the diluents and one of the binders. The excipients and active pharmaceutical ingredient were characterized in terms of multiple variables, and principal properties were calculated with principal component analysis. A Plackett and Burman design was applied to the principal properties. The relationships between the design factors and two responses, mean disintegration time and mean crushing strength, were evaluated by using regression methods. Both formulations were found to be robust under controlled conditions.

Chemistry, Pharmaceutical↗

PubMed2006

A potent serotonin-modulating compound AP-267 attenuates morphine withdrawal-induced blood-brain barrier dysfunction in rats.

The possibility that a serotonin 5-HT2c receptor-modulating compound, AP-267, will influence spontaneous morphine withdrawal symptoms and the alterations in the brain fluid microenvironment was examined in a rat model. Daily administration of morphine (10 mg/kg, i.p.) for 10 days resulted in dependence of rats as seen by loss of analgesic response. On the 11th day, no morphine administration was given. This resulted in profound withdrawal symptoms 24 h after morphine withdrawal. The magnitude and severity of these symptoms were increased further 48 h after withdrawal. Measurement of the blood-brain barrier (BBB) permeability, a measure of perturbed brain fluid microenvironment showed leakage of Evans blue and radioiodine tracers in several parts of the brain in rats showing withdrawal symptoms. Whereas, rats treated with AP-267 either on the 1st day or 2nd day morphine withdrawal showed much less symptoms and leakage of the BBB. Taken together, these observations suggest that (a) stress associated with the withdrawal symptoms are sufficient enough to induce breakdown of the BBB function, and (b) modulation of serotonin 5-HT2c receptors may have some protective influence on the stress symptoms and the BBB disruption.

Animals↗

PubMed2004

Using chemometrics for navigating in the large data sets of genomics, proteomics, and metabonomics (gpm).

This article describes the applicability of multivariate projection techniques, such as principal-component analysis (PCA) and partial least-squares (PLS) projections to latent structures, to the large-volume high-density data structures obtained within genomics, proteomics, and metabonomics. PCA and PLS, and their extensions, derive their usefulness from their ability to analyze data with many, noisy, collinear, and even incomplete variables in both X and Y. Three examples are used as illustrations: the first example is a genomics data set and involves modeling of microarray data of cell cycle-regulated genes in the microorganism Saccharomyces cerevisiae. The second example contains NMR-metabonomics data, measured on urine samples of male rats treated with either of the drugs chloroquine or amiodarone. The third and last data set describes sequence-function classification studies in a set of G-protein-coupled receptors using hierarchical PCA.

Animals↗

PubMed2004

Synthesis and quantitative structure-activity relationship of hydrazones of N-amino-N'-hydroxyguanidine as electron acceptors for xanthine oxidase.

A series of new N-hydroxyguanidines were synthesized and tested for electron acceptor activity on bovine milk xanthine oxidase using xanthine as reducing substrate. Manual inspection of the structure-activity data revealed that molecules containing nitro groups ("set A") show a different structure-activity relationship pattern compared to non-nitro compounds ("set B"). Accordingly separate QSAR models were built and validated for the two sets. Substantial differences were found in properties governing acceptor activity for the models, the only common property being sterical access to the imino nitrogen atom of the hydroxyguanidinimines. For set A molecules the presence of a nitro substituent at a certain distance range from the hydroxuguanidino group was most important. In addition, the presence of a nitro group in the ortho position interacting with NH(2) of the hydroxyguanidino group, and the mutual geometry of the phenyl ring, hydroxyguanidine, and imine groups was important for this set. By contrast, for set B molecules the acceptor activity was most influenced by the geometry of methoxy groups and the size and geometry of meta and para substituents of the phenyl ring.

Animals↗

PubMed2004

Multivariate methods in the development of a new tablet formulation: optimization and validation.

In a previous study of the development of a tablet formulation approximately 100 excipients were characterized in screening experiments using multivariate design. Acceptable values for important responses were obtained with some of the formulations. The relationships between the properties of the excipients and the responses were evaluated using PLS. In this study additional experiments were performed in order to validate models obtained from the screening study and to find a formulation of suitable composition with desired tablet properties. A formulation with the desired disintegration time was found with the additional experiments and the agreement between observed and predicted values was fair for the tablets that did disintegrate. A limitation of this study was that tablets from four experiments did not disintegrate within the set time limit. The lack of agreement between observed and predicted values of these four experiments was probably due to the nature of one of the factors in the design. Considering the reduced experimental design the results are still encouraging.

Chemistry, Pharmaceutical↗

PubMed2003

Multivariate methods in the development of a new tablet formulation.

The overall objective of this article is to use an efficient approach to find a suitable tablet formulation for direct compression. By using traditional approaches to statistical experimental design in tablet formulation, the number of experiments quickly grows when many descriptive variables or many excipients are included. To facilitate the screening process, a multivariate design, which allows a systematical evaluation of a large number of excipients with a limited number of experiments, was implemented. Formulations with acceptable values for disintegration time and crushing strength were obtained with some of the formulations in the present study. The multivariate experimental design strategy yielded PLS models that will be used to identify a region of interest for the optimization. The strategy is general and can be applied in many different areas of pharmaceutical research and development.

Drug Design↗

PubMed2002

The novel guanidine ME10092 protects the heart during ischemia-reperfusion.

The novel guanidine N-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine [ME10092; a metabolite to the strongly cardioprotective hydroxyguanidine N-(3,4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine (PR5)] was administered intravenously to rats subjected to left coronary artery clamping followed by reperfusion. Administration of 1-10 mg/kg of ME10092 1 or 5 min before 10 min of coronary artery occlusion followed by 20 min reperfusion significantly and dose-dependently inhibited the reperfusion-induced burst of arrhythmia, and markedly improved the survival of the animals. This dose schedule also dose-dependently and significantly inhibited the ST-segment elevation seen on the ECG during the artery occlusion, and attenuated the secondary rise in ST-segment during the reperfusion. Even when ME10092 was administered 5 min after the start of the reperfusion, the ST-segment elevation became significantly attenuated. Administration of ME10092 (3 plus 1.5 mg/kg) to animals subjected to 1 h left coronary occlusion followed by 2 h reperfusion reduced the heart infarction size by about 40%. ME10092 also dose-dependently reduced the heart rate, both during normal conditions and during ischemia and reperfusion. Moreover, the highest dose of ME10092 used (10 mg/kg) strongly attenuated the reduction in blood pressure seen during 10 min left coronary occlusion, as well as it attenuated the rebound rise in blood pressure seen during the 20 min reperfusion phase; that is, resulting in a normalisation of the blood pressure disturbances caused by the ischemia-reperfusion. We also showed that after its p.o. administration, the PR5 hydroxyguanidine became completely metabolised to its guanidine ME10092, with no detectable traces of PR5 being present 30 and 60 min after the administration. Moreover, after the p.o. administration of ME10092, no signs of the formation of PR5 were seen on analysis of the rats' plasma. In view of the practically indistinguishable pharmacological effects of ME10092 and PR5, we suggest the strong cardioprotective effects of these compounds to be mediated by a direct effect by ME10092 per se.

Animals↗

PubMed2002

Proteo-chemometrics analysis of MSH peptide binding to melanocortin receptors.

The published data for six melanocortin peptides binding to wild-type and chimeric melanocortin MC(1)/MC(3) receptors were analysed using the novel proteo-chemometrics modelling approach. The chimeric receptors and the peptides were coded using binary descriptors and used to correlate with the experimental data for affinity or selectivity for peptides binding to receptors. Correlations were achieved using partial least squares projection to latent structures (PLS) and statistically valid models were obtained. The models were further improved by adding cross-terms and applying orthogonal signal correction. The models were validated using external prediction, with half of the data being excluded from the modelling. Interpretation of the results using PLS coefficient plots revealed that the binding pocket for the melanocortins is located between the first, second, third, sixth and seventh transmembrane regions of the melanocortin receptors, in good agreement with previous three-dimensional models for the interactions of melanocortins with melanocortin receptors. Further, analysis of cross-terms between peptide descriptors indicated that the proteo-chemometrics modelling is able to distinguish between differences in the conformational space of the peptides that affect binding affinity and selectivity.

Humans↗

PubMed2002

Classification of G-protein coupled receptors by alignment-independent extraction of principal chemical properties of primary amino acid sequences.

We have developed an alignment-independent method for classification of G-protein coupled receptors (GPCRs) according to the principal chemical properties of their amino acid sequences. The method relies on a multivariate approach where the primary amino acid sequences are translated into vectors based on the principal physicochemical properties of the amino acids and transformation of the data into a uniform matrix by applying a modified autocross-covariance transform. The application of principal component analysis to a data set of 929 class A GPCRs showed a clear separation of the major classes of GPCRs. The application of partial least squares projection to latent structures created a highly valid model (cross-validated correlation coefficient, Q(2) = 0.895) that gave unambiguous classification of the GPCRs in the training set according to their ligand binding class. The model was further validated by external prediction of 535 novel GPCRs not included in the training set. Of the latter, only 14 sequences, confined in rapidly expanding GPCR classes, were mispredicted. Moreover, 90 orphan GPCRs out of 165 were tentatively identified to GPCR ligand binding class. The alignment-independent method could be used to assess the importance of the principal chemical properties of every single amino acid in the protein sequences for their contributions in explaining GPCR family membership. It was then revealed that all amino acids in the unaligned sequences contributed to the classifications, albeit to varying extent; the most important amino acids being those that could also be determined to be conserved by using traditional alignment-based methods.

Amino Acids↗

PubMed2002

Proteochemometrics modeling of the interaction of amine G-protein coupled receptors with a diverse set of ligands.

We have evaluated the proteochemometrics approach in the analysis of the interactions of a diverse set or organic ligands with subtypes of serotonin, dopamine, histamine, and adrenergic receptors. As used herein, proteochemometrics exploits affinity data for series of organic amines binding to wild-type amine G protein-coupled receptors, correlating it to descriptions and cross-description derived from the primary amino acid sequences of the receptors and the computed structures of the organic compounds. We show that after appropriate data preprocessing, statistically valid models that have good external predictive ability can be created. Evaluation of the models gave important quantitative insight into the mode of interactions of the amine G protein-coupled receptors with their ligands.

Amino Acids↗